Crystalization of pharmaceutical compounds

ABSTRACT

Novel crystalline forms of tadalafil suitable for pharmaceutical compositions in drug delivery systems for humans.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of application Ser. No. 13/203,297,filed Nov. 11, 2011, which claims priority to PCT InternationalApplication No. PCT/US2010/025421, filed Feb. 25, 2010, which claimspriority to U.S. Provisional Application No. 61/208,624, filed Feb. 26,2009, all of which is incorporated herein by reference.

TECHNICAL FIELD

The invention pertains to novel crystalline forms of the drug tadalafil,as well as methods for their preparation and use. One or more of theseforms can be used as a solid dosage form in pharmaceutical compositionsin a variety of drug delivery systems.

BACKGROUND OF THE INVENTION

Tadalafil is known as(6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2methyl-pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, has theformula C₂₂H₁₉N₃O₄ representing a molecular weight of 389.41 g/mol andis depicted by the following chemical structure:

Tadalafil was originally developed by ICOS in 1994 and marketed viacollaboration with Eli Lilly that subsequently took over ICOS in 2007.Tadalafil is a white solid particulate material that is practicallyinsoluble in water. It is sparingly soluble in tetrahydrofuran andchloroform but is soluble in dioxane. Tadalafil has an apparentpartition coefficient (log P)_(app)=1.7 in n-octanol/buffer pH 7.4.

Tadalafil, currently used for the treatment of erectile dysfunction (ED)under the Cialis® brand name, is a cGMP (cyclic gaunosine monophosphate)specific phosphodiesterase 5 (PDE5) inhibitor which enhances the effectof nitric oxide at the nerve ending and endothelial cells in the corpuscavernosum by inhibiting phosphodiesterase type 5 in the corpuscavernosum of the penis. This results in vasodilation, increased inflowof blood into the corporus cavernosum, and ensuing penile erection uponsexual stimulation. Tadalafil is also being investigated currently as atreatment for pulmonary hypertension. For ED treatment tadalafil ismanufactured as a tablet for daily use (2.5 and 5 mg) with doses rangingfrom 5-20 mg as needed. See Cialis® Prescribing Information, February2010. Tadalafil, the method of preparing tadalafil, its therapeuticuses, and pharmaceutical compositions containing it are described inU.S. Pat. Nos. 5,859,006; 6,140,329; 6,821,975; 6,943,166; and 7,182,958which are incorporated herein by reference in their entirety.

A major limitation on its use to treat ED, which could be due in part toits very low aqueous solubility, is the fact that tadalafil takes from0.5 to 6 hours (Tmax) to achieve the mean peak plasma concentration(Cmax) regardless of food intake. Therefore enhancing the aqueoussolubility and subsequently the rate of dissolution can lead to ashortened Tmax and produce a quicker onset of action. In addition, thisreduces the residence time in the GI tract and decreases the possibilityof producing undesirable side effects through long contact with the GImembrane.

Different crystalline polymorphic forms of tadalafil have been disclosedin the literature (see for example U.S. Patent application 2006/0111571A1). There are eight known polymorphs including forms II and III whichare acetone and methylethyl ketone solvates, respectively.

In general, active pharmaceutical ingredients (APIs) in pharmaceuticalcompositions can be prepared in a variety of different chemical formsincluding chemical derivatives, solvates, hydrates, cocrystals and/orsalts. Such compounds can also be prepared in different physical formsof the same chemical composition. For example, they may be amorphous,may have different crystalline forms (polymorphs), and/or may exist indifferent solvated or hydrated states with no change in the chemicalcomposition of the original API. The discovery of new crystalline formsof a pharmaceutically useful compound may provide an opportunity toimprove the physico-chemical characteristics and subsequently theclinical performance of such a compound. Additionally it expands thearray of resources available for designing, for example, apharmaceutical dosage form of an API with a targeted/sustained releaseprofile or improved shelf life due to higher physical stability,improved particle size or size distribution, or powder flowability andhandling for easier downstream processing or even for changing its routeof delivery.

For example, crystalline forms of the same chemical composition(polymorphs) can have different aqueous solubilities from one another,where typically the more thermodynamically stable the polymorph the lesssoluble it becomes. In addition, polymorphs of an API can also differ inphysico-chemical properties such as solid phase stability, highershelf-life, bioavailability, particle morphology, vapor pressure,density, color, melting point and compressibility. However, it issometimes difficult to produce the desired polymorph consistently orthere is little improvement in their aqueous solubility orcharacterizing of all polymorphic forms can be challenging. In addition,if only one polymorph is discovered then there is less opportunity tomanipulate and improve physico-chemical properties of the API. Theselimitations can adversely affect the API formulation into a usabledosage form or even force pharmaceutical companies to abandon the API'sdevelopment.

Therefore it would be highly appreciable to generate novel crystallinemolecular complexes, such as cocrystals, that can address suchlimitations and enhance the properties of an API such as aqueoussolubility, rate of dissolution, bioavailability, Cmax, Tmax, solidphase stability, shelf life, downstream processibility (e.g.flowability, compressibility, degree of brittleness, particle size andsize distribution), crystallization of amorphous compounds, decreasepolymorphic form diversity, reduce toxicity, taste masking, and/or itsproduction and manufacturing methods efficiency. For oral delivery ofsolid dosage forms, it is frequently advantageous to have novelcrystalline forms of drug materials that possess such improvedproperties and particularly increased aqueous solubility and solid phasestability. It is also desirable in general to increase the dissolutionrate of such solid forms, increase bioavailability, and provide a morerapid onset to quicken the therapeutic effect. In addition, it is usefulto have a crystal form which, when administered to a subject, reaches apeak plasma level faster and has a longer lasting therapeutic plasmaconcentration, when compared to other existing forms on a dose-for-dosebasis.

Because of the limitations related to the low aqueous solubility oftadalafil, there is a need to develop novel forms that have improvedphysico-chemical properties including aqueous solubility, which can beformulated for use in oral administration to achieve faster onset orpossibly improve its clinical profile.

It is possible to tackle these limitations by generating novelcrystalline forms of tadalafil that includes crystalline molecularcomplexes, such as cocrystals, thereof that can improve the rate ofdissolution, shorten Tmax, achieve rapid onset and reduce residence timein the GI tract.

SUMMARY OF THE INVENTION

The invention is directed towards generating novel compositions andcrystalline forms of tadalafil that could improve aqueous solubility,rate of dissolution and/or shorten Tmax. One aspect of the presentinvention includes novel crystalline molecular complexes of tadalafil,such as cocrystals, and mixtures containing such materials. In addition,the invention further includes methods for the preparation of suchcomplexes and compositions of crystalline molecular complexes oftadalafil suitable as an API (active pharmaceutical ingredient) in apharmaceutical dosage form. Specific molecular complexes pertaining tothe disclosure include, but are not limited to, complexes of tadalafilwith oxalic acid, 4-hydroxybenzoic acid, malonic acid, 3-phenylpropanoicacid, methylparaben and propylparaben.

The foregoing and other features and advantages of the invention willbecome more apparent from the following detailed description, whichproceeds with reference to the accompanying drawings. Such descriptionis meant to be illustrative, and not limiting, of the invention. Obviousvariants of the disclosed tadalafil forms in the text, including thosedescribed by the drawings and examples will be readily apparent to theperson of ordinary skill in the art having the present disclosure, andsuch variants are considered to be a part of the current invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a PXRD diffractogram of a crystalline tadalafil and oxalicacid molecular complex (1:1).

FIG. 2 shows an FTIR spectrum of a crystalline tadalafil and oxalic acidmolecular complex (1:1).

FIG. 3 shows a PXRD diffractogram of a crystalline tadalafil and4-hydroxybenzoic acid molecular complex (1:2).

FIG. 4 shows an FTIR spectrum of a crystalline tadalafil and4-hydroxybenzoic acid molecular complex (1:2).

FIG. 5 shows a PXRD diffractogram of a crystalline tadalafil and3-phenylpropanoic acid molecular complex (1:1).

FIG. 6 shows an FTIR spectrum of a crystalline tadalafil and3-phenylpropanoic acid molecular complex (1:1).

FIG. 7 shows a PXRD diffractogram of a crystalline tadalafil and malonicacid molecular complex (1:1).

FIG. 8 shows an FTIR spectrum of a crystalline tadalafil and malonicacid molecular complex (1:1).

FIG. 9 shows a PXRD diffractogram of a crystalline tadalafil andmethylparaben molecular complex (1:1).

FIG. 10 shows an FTIR spectrum of a crystalline tadalafil andmethylparaben molecular complex (1:1).

FIG. 11 shows a PXRD diffractogram of a crystalline tadalafil andpropylparaben molecular complex (1:1).

FIG. 12 shows an FTIR spectrum of a crystalline tadalafil andpropylparaben molecular complex (1:1).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides new crystalline molecular complexes, such ascocrystals, of tadalafil to improve its physico-chemical characteristicsand possible clinical profiles. For example, as discussed above, a newcrystalline form is particularly advantageous if it can improve theaqueous solubility of tadalafil. Additionally, the crystal propertiesconferred upon the new crystal forms are also useful when thebioavailability is improved and its plasma concentration and/or serumconcentration is improved which is particularly advantageous for orallydelivered formulations.

A number of novel tadalafil crystalline forms have been synthesized,characterized, and disclosed herein. The novel tadalafil crystallineforms may be formulated in pharmaceutical dosage forms as known in theart for tadalafil and administered for the same therapeutic uses. Thetechniques and approaches set forth herein can further be used by theperson of ordinary skill in the art to prepare obvious variants thereof,said variants considered to be part of the inventive disclosure.

Accordingly, in a first aspect, the invention relates to crystallinemolecular complexes of tadalafil with a co-former. The co-former may bea short-chain short to medium chain organic acid , such as oxalic acidor malonic acid; a hydroxybenzoic acid or a hydroxybenzoic acid ester,such as 4-hydroxybenzoic acid, salicylic acid, methylparaben, apropylparaben (e.g. n-propylpraben, isopropylparaben); or a phenylalkanoic acid, such as 3-phenylpropanoic acid. Other possible co-formersare described in U.S. Pat. No. 7,452,555 and U.S. Patent Application2003/0224006 A1, which are incorporated here by reference. The molarratio of the co-former in the molecular complex may range from 1:3 to3:1 or preferably 1:2 to 2:1. The crystalline molecular complexes may beprepared using known techniques such as dry or solvent grinding,heating, slurrying or solvent evaporation of their solution in single ormixed solvent systems.

In one aspect, the invention relates to a 1:1 crystalline molecularcomplex of tadalafil with methylparaben. As shown in the examples belowa 1:1 crystalline molecular complex of tadalafil and methylparaben maybe prepared by dry grinding or in a solvent slurry. As tadalafil andmethylparaben have been shown to cocrystallize, this crystallinemolecular complex of the invention may also be prepared by othertechniques known in the art such as, but not limited to, solventgrinding, heating, or solvent evaporation of their solution in single ormixed solvent systems.

Another aspect of the invention relates to a 1:1 crystalline molecularcomplex of tadalafil with propylparaben. As shown in the examples belowa 1:1 crystalline molecular complex of tadalafil and propylparaben maybe prepared by dry grinding or in a solvent slurry. As tadalafil andmethylparaben have been shown to cocrystallize, this crystallinemolecular complex of the invention may also be prepared by othertechniques known in the art such as, but not limited to, solventgrinding, heating, or solvent evaporation of their solution in single ormixed solvent systems.

Another aspect of the invention relates to a 1:2 crystalline molecularcomplex of tadalafil with 4-hydroxybenzoic acid. As shown in theexamples below a 1:2 crystalline molecular complex of tadalafil and4-hydroxybenzoic acid may be prepared by dry grinding or in a solventslurry. As tadalafil and 4-hydroxybenzoic acid have been shown tococrystallize, this crystalline molecular complex of the invention mayalso be prepared by other techniques known in the art such as, but notlimited to, solvent grinding, heating, or solvent evaporation of theirsolution in single or mixed solvent systems.

Another aspect of the invention relates to a 1:1 crystalline molecularcomplex of tadalafil with malonic acid. As shown in the examples below a1:1 crystalline molecular complex of tadalafil and malonic acid may beprepared by dry grinding or in a solvent slurry. As tadalafil andmalonic acid have been shown to cocrystallize, this crystallinemolecular complex of the invention may also be prepared by othertechniques known in the art such as, but not limited to, solventgrinding, heating, or solvent evaporation of their solution in single ormixed solvent systems.

Another aspect of the invention relates to a 1:1 crystalline molecularcomplex of tadalafil with oxalic acid. As shown in the examples below a1:1 crystalline molecular complex of tadalafil and oxalic acid may beprepared by dry grinding. As tadalafil and oxalic acid have been shownto cocrystallize, this crystalline molecular complex of the inventionmay also be prepared by other techniques known in the art such as, butnot limited to, solvent grinding, heating, a solvent slurry, or solventevaporation of their solution in single or mixed solvent systems.

Another aspect of the invention relates to a 1:1 crystalline molecularcomplex of tadalafil with 3-phenylpropanoic acid. As shown in theexamples below a 1:1 crystalline molecular complex of tadalafil and3-phenylpropanoic acid may be prepared by dry grinding or in a solventslurry. Another aspect of the invention provides a crystalline molecularcomplex of tadalafil and 3-phenylpropanoic acid by dissolving bothcompounds in acetonitrile and allowing the solvent mixtures toevaporate. As tadalafil and 3-phenylpropanoic acid have been shown tococrystallize, this crystalline molecular complex of the invention mayalso be prepared by other techniques known in the art such as, but notlimited to, solvent grinding, heating, or solvent evaporation of theirsolution in single or mixed solvent systems.

Another aspect of the invention provides crystalline molecular complexesof tadalafil as discussed above and, as particular examples, crystallinemolecular complexes with 4-hydroxybenzoic acid, malonic acid, oxalicacid, 3-phenylpropanoic acid, methylparaben and propylparaben, suitablefor pharmaceutical formulations than can be delivered via differentroutes to the human body. In addition to the crystalline molecularcomplex such pharmaceutical formulations may include one or morepharmaceutically acceptable carriers, including, without limitation,binders, fillers, lubricants, emulsifiers, suspending agents,sweeteners, flavorings, preservatives, buffers, wetting agents,disintegrants, effervescent agents and other conventional excipients andadditives. The crystalline tadalafil molecular complexes of theinvention and pharmaceutical formulations containing them may be used inthe same therapies known for tadalafil itself. Pharmaceuticalformulations of tadalafil, its therapeutic uses, and methods oftreatment are described U.S. Pat. Nos. 5,859,006; 6,140,329; 6,821,975;6,943,166; and 7,182,958 as mentioned above.

EXAMPLES

The following examples illustrate the invention without intending tolimit its scope.

Preparative Examples

Tadalafil as a starting material used in all experiments in thisdisclosure was supplied by Beijing Apifocus Co. Ltd., China with statedchemical purity of 99.9%. Further purification through recrystallizationfrom a solvent such as THF was needed to improve crystallinity and getrid of suspected physical impurities that could interfere with solidphase characterization.

Example 1 Preparation of Tadalafil and Oxalic Acid Complex (1:1)

120 mg of tadalafil was ground with 28 mg of oxalic acid and 20 μL ofacetonitrile was added to the solid mixture. The solids gathered aftergrinding were stored in screw cap vials for subsequent analysis.

Example 2 Preparation of Tadalafil and 4-Hydroxybenzoic Acid Complex(1:2)

123.2 mg of tadalafil was ground with 88.3 mg of 4-hydroxybenzoic acidand 40 μL of acetonitrile was added to the solid mixture. The solidsgathered after grinding were stored in screw cap vials for subsequentanalysis.

Example 3 Preparation of Tadalafil and 4-Hydroxybenzoic Acid Complex(1:2) by Slurry Method

1000 mg of tadalafil was slurried with 710 mg of 4-hydroxybenzoic acidand 5 mL of acetonitrile. The solids gathered after the slurry weredried and stored in a screw cap vial for subsequent analysis.

Example 4 Preparation of Tadalafil and 3-Phenylpropanoic Acid Complex(1:1)

110 mg of tadalafil was ground with 42 mg of 3-phenylpropanoic acid and20 μL of acetonitrile was added to the solid mixture. The solidsgathered after grinding were stored in screw cap vials for subsequentanalysis.

Example 5 Preparation of Tadalafil and 3-Phenylpropanoic Acid Complex(1:1) by Slurry Method

50 mg of tadalafil was slurried with 288.75 mg of 3-phenylpropanoic acidand 1 mL of acetonitrile. The solids gathered after the slurry weredried and stored in a screw cap vial for subsequent analysis.

Example 6 Preparation of Tadalafil and Malonic Acid Complex (1:1)

110 mg of tadalafil was ground with 30 mg of malonic acid and 40 μL ofacetonitrile was added to the solid mixture. The solids gathered aftergrinding were stored in screw cap vials for subsequent analysis.

Example 7 Preparation of Tadalafil and Malonic Acid Complex (1:1) bySlurry Method

200 mg of tadalafil was slurried with 212 mg of malonic acid and 1 mL ofacetonitrile. The solids gathered after the slurry were dried and storedin a screw cap vial for subsequent analysis.

Example 8 Preparation of Tadalafil and Methylparaben Complex (1:1)

100 mg of tadalafil was ground with 39 mg of methylparaben and 20 μL ofacetonitrile was added to the solid mixture. The solids gathered aftergrinding were stored in screw cap vials for subsequent analysis.

Example 9 Preparation of Tadalafil and Methylparaben Complex (1:1) bySlurry Method

200 mg of tadalafil was slurried with 156 mg of methylparaben and 1 mLof acetonitrile. The solids gathered after the slurry were dried andstored in a screw cap vial for subsequent analysis.

Example 10 Preparation of Tadalafil and Propylparaben Complex (1:1)

100 mg of tadalafil was ground with 46 mg of propylparaben and 20 μL ofacetonitrile was added to the solid mixture. The solids gathered aftergrinding were stored in screw cap vials for subsequent analysis.

Example 11 Preparation of Tadalafil and Propylparaben Complex (1:1) bySlurry Method

200 mg of tadalafil was slurried with 184 mg of propylparaben and 1 mLof acetonitrile. The solids gathered after the slurry were dried andstored in a screw cap vial for subsequent analysis.

Characterization Examples

Analytical techniques used to observe the crystalline forms includeFourier Transform FTIR Spectroscopy (FTIR) and powder X-ray diffraction(PXRD). The particular methodology used in such analytical techniquesshould be viewed as illustrative, and not limiting in the context ofdata collection. For example, the particular instrumentation used tocollect data may vary; routine operator error or calibration standardsmay vary; sample preparation method may vary (for example, the use ofthe KBr disk or Nujol mull technique for FTIR analysis).

Powder X-Ray Diffraction (PXRD)

All cocrystal products were observed by a D-8 Bruker X-ray PowderDiffraction using Cu Kα (λ=1.540562 Å), 40 kV, 40 mA. The data wascollected over an angular range of 3 to 40 °2θ in continuous scan modeusing a step size of 0.05 °2θ and a scan speed of 1.0°/min. Peaks arereported at °2θ±0.2 °2θ.

Fourier Transform FTIR Spectroscopy (FTIR)

FTIR analysis was performed on a Perkin Elmer Spectrum 100 FTIRspectrometer equipped with a solid-state ATR accessory. Peaks arereported at cm⁻¹±1 cm⁻¹.

Example 12 Characterization of Tadalafil and Oxalic Acid Complex (1:1)

The PXRD diffractogram of a tadalafil and oxalic acid complex (1:1) isshown in FIG. 1. Table 1 below lists representative peaks from the PXRDpattern of FIG. 1. The representative peaks in Table 1 or a subset ofthose peaks, as well as the peaks shown in FIG. 1 or a subset of thosepeaks, can be used to characterize the tadalafil and oxalic acidcrystalline molecular complex (1:1) of the invention.

FIG. 2 shows an FTIR spectrum of a tadalafil and oxalic acid complex(1:1). Table 2 below lists representative peaks from the FTIR spectrumof FIG. 2. The representative peaks in Table 2 or a subset of thosepeaks, as well as the peaks shown in FIG. 2 or a subset of those peaks,can be used to characterize the tadalafil and oxalic acid crystallinemolecular complex (1:1) of the invention.

Example 13 Characterization of Tadalafil and 4-Hydroxybenzoic AcidComplex (1:2)

The PXRD diffractogram of a tadalafil and 4-hydroxybenzoic acid complex(1:2) is shown in FIG. 3. Table 1 below lists representative peaks fromthe PXRD pattern of FIG. 3. The representative peaks in Table 1 or asubset of those peaks, as well as the peaks shown in FIG. 3 or a subsetof those peaks, can be used to characterize the tadalafil and4-hydroxybenzoic acid crystalline molecular complex (1:2) of theinvention.

FIG. 4 shows an FTIR spectrum of a tadalafil and 4-hydroxybenzoic acidcomplex (1:2). Table 2 below lists representative peaks from the FTIRspectrum of FIG. 4. The representative peaks in Table 2 or a subset ofthose peaks, as well as the peaks shown in FIG. 4 or a subset of thosepeaks, can be used to characterize the tadalafil and 4-hydroxybenzoicacid crystalline molecular complex (1:2) of the invention.

Example 14 Characterization of Tadalafil and 3-Phenylpropanoic AcidComplex (1:1)

The PXRD diffractogram of a tadalafil and 3-phenylpropanoic acid complex(1:1) is shown in FIG. 5. Table 1 below lists representative peaks fromthe PXRD pattern of FIG. 5. The representative peaks in Table 1 or asubset of those peaks, as well as the peaks shown in FIG. 5 or a subsetof those peaks, can be used to characterize the tadalafil and3-phenylpropanoic acid crystalline molecular complex (1:1) of theinvention.

FIG. 6 shows an FTIR spectrum of a tadalafil and 3-phenylpropanoic acidcomplex (1:1). Table 2 below lists representative peaks from the FTIRspectrum of FIG. 6. The representative peaks in Table 2 or a subset ofthose peaks, as well as the peaks shown in FIG. 6 or a subset of thosepeaks, can be used to characterize the tadalafil and 3-phenylpropanoicacid crystalline molecular complex (1:1) of the invention.

Example 15 Characterization of Tadalafil and Malonic Acid Complex (1:1)

The PXRD diffractogram of a tadalafil and malonic acid complex (1:1) isshown in FIG. 7. Table 1 below lists representative peaks from the PXRDpattern of FIG. 7. The representative peaks in Table 1 or a subset ofthose peaks, as well as the peaks shown in FIG. 7 or a subset of thosepeaks, can be used to characterize the tadalafil and malonic acidcrystalline molecular complex (1:1) of the invention.

FIG. 8 shows an FTIR spectrum of a tadalafil and malonic acid complex(1:1). Table 2 below lists representative peaks from the FTIR spectrumof FIG. 8. The representative peaks in Table 2 or a subset of thosepeaks, as well as the peaks shown in FIG. 8 or a subset of those peaks,can be used to characterize the tadalafil and malonic acid crystallinemolecular complex (1:1) of the invention.

Example 16 Characterization of Tadalafil and Methylparaben Complex (1:1)

The PXRD diffractogram of a tadalafil and methylparaben complex (1:1) isshown in FIG. 9. Table 1 below lists representative peaks from the PXRDpattern of FIG. 9. The representative peaks in Table 1 or a subset ofthose peaks, as well as the peaks shown in FIG. 9 or a subset of thosepeaks, can be used to characterize the tadalafil and methylparabencrystalline molecular complex (1:1) of the invention.

FIG. 10 shows an FTIR spectrum of a tadalafil and methylparaben complex(1:1). Table 2 below lists representative peaks from the FTIR spectrumof FIG. 10. The representative peaks in Table 2 or a subset of thosepeaks, as well as the peaks shown in FIG. 10 or a subset of those peaks,can be used to characterize the tadalafil and methylparaben crystallinemolecular complex (1:1) of the invention.

Example 17 Characterization of Tadalafil and Propylparaben Complex (1:1)

The PXRD diffractogram of a tadalafil and propylparaben complex (1:1) isshown in FIG. 11. Table 1 below lists representative peaks from the PXRDpattern of FIG. 11. The representative peaks in Table 1 or a subset ofthose peaks, as well as the peaks shown in FIG. 11 or a subset of thosepeaks, can be used to characterize the tadalafil and propylparabencrystalline molecular complex (1:1) of the invention.

FIG. 12 shows an FTIR spectrum of a tadalafil and propylparaben complex(1:1). Table 2 below lists representative peaks from the FTIR spectrumof FIG. 12. The representative peaks in Table 2 or a subset of thosepeaks, as well as the peaks shown in FIG. 12 or a subset of those peaks,can be used to characterize the tadalafil and propylparaben crystallinemolecular complex (1:1) of the invention.

TABLE 1 PXRD Peaks, (°2θ ± 0.2 °2θ). Tadalafil:4-Hydroxy-Tadalafil:3-Phenyl- Tadalafil:Malonic Tadalafil:Methyl-Tadalafil:Propyl- Tadalafil:Oxalic benzoic propanoic Acid parabenparaben Acid (1:1) Acid (1:2) Acid (1:1) (1:1) (1:1) (1:1) 8.8 7.9 5.510.5 5.3 5.2 13.6 14.4 10.1 13.5 11.6 10.5 15.6 17.7 15.6 15.1 16.2 15.318.0 18.8 19.5 16.8 20.4 18.7 20.8 19.5 21.6 19.0 22.0 20.6 22.4 24.523.0 24.0 24.2 22.0 25.1 25.0 25.5 26.0 28.2 24.5

TABLE 2 IR Peaks, (cm⁻¹ ± 1 cm⁻¹). Tadalafil:Oxalic Tadalafil:4-Hydroxy-Tadalafil:3-Phenyl- Tadalafil:Malonic Tadalafil:Methyl-Tadalafil:Propyl- Acid benzoic propanoic Acid paraben paraben (1:1) Acid(1:2) Acid (1:1) (1:1) (1:1) (1:1) 921 849 748 748 747 747 1032 921 9191037 1225 1098 1241 1271 1143 1246 1266 1271 1441 1441 1432 1649 14321433 1637 1606 1645 1767 1646 1645 1784 1647 1737 3091 1706 1700 33161672 3324 3350 3343 3338

1. A crystalline molecular complex of tadalafil comprising tadalafil anda co-former.
 2. A crystalline molecular complex of tadalafil accordingto claim 1, wherein the co-former is selected from the group consistingof a short to medium chain organic acids, alcohols and amines.
 3. Acrystalline molecular complex of tadalafil according to claim 1 where inthe molar ratio of the co-former in the complex ranges from 1:3 to 3:1.4. A crystalline molecular complex of tadalafil selected from the groupconsisting of molecular complex of tadalafil and oxalic acid, molecularcomplex of tadalafil and 4-hydroxybenzoic acid, molecular complex oftadalafil and 3-phenylpropanoic acid; molecular complex of tadalafil andmalonic acid; molecular complex of tadalafil and methylparaben; andmolecular complex of tadalafil and propylparaben.
 5. A crystallinemolecular complex of tadalafil and oxalic acid of claim 4, wherein themolecular complex is characterized by: an X-ray powder diffractogramhaving peaks at 8.8, 13.6, 15.6, 18.0, 20.8, 22.4, and 25.1 °2θ±0.2 °2θ;an infra-red spectrum having peaks at 921, 1032, 1241, 1441, 1637, 1784,and 3316 cm⁻¹±1 cm⁻¹; or both.
 6. A pharmaceutical compositioncomprising a crystalline molecular complex of tadalafil and oxalic acidof claim 5 and a pharmaceutically acceptable carrier.
 7. A crystallinemolecular complex of tadalafil and 4-hydroxybenzoic acid of claim 4,wherein the molecular complex is characterized by: an X-ray powderdiffractogram having peaks at 7.9, 14.4, 17.7, 18.8, 19.5, 24.5, and25.0 °2θ±0.2 °2θ; an infra-red spectrum having peaks at 849, 921, 1271,1441, 1606, 1647 and 1672 cm⁻¹±1 cm⁻¹; or both.
 8. A pharmaceuticalcomposition comprising a crystalline molecular complex of tadalafil and4-hydroxybenzoic acid of claim 7 and a pharmaceutically acceptablecarrier.
 9. A crystalline molecular complex of tadalafil and3-phenylpropanoic acid of claim 4, wherein the crystalline molecularcomplex is characterized by: an X-ray powder diffractogram having peaksat 5.5, 10.1, 15.6, 19.5, 21.6, 23.0, and 25.5 °2θ±0.2 °2θ; an infra-redspectrum having peaks at 748, 919, 1143, 1432, 1645, 1737, and 3324cm⁻¹±1 cm⁻¹; or both.
 10. A pharmaceutical composition comprising acrystalline molecular complex of tadalafil and 3-phenylpropanoic acid ofclaim 9 and a pharmaceutically acceptable carrier.
 11. A crystallinemolecular complex of tadalafil and malonic acid of claim 4, wherein themolecular complex is characterized by: an X-ray powder diffractogramhaving peaks at 10.5, 13.5, 15.1, 16.8, 19.0, 24.0, and 26.0 °2θ±0.2°2θ; an infra-red spectrum having peaks at 748, 1037, 1246, 1649, 1767,3091, and 3350 cm⁻¹±1 cm ⁻¹; or both.
 12. A pharmaceutical compositioncomprising a crystalline molecular complex of tadalafil and malonic acidof claim 11 and a pharmaceutically acceptable carrier.
 13. A crystallinemolecular complex of tadalafil and methylparaben of claim 4, wherein themolecular complex is characterized by: an X-ray powder diffractogramhaving peaks at 5.3, 11.6, 16.2, 20.4, 22.0, 24.2, and 28.2 °2θ±0.2 °2θ;an infra-red spectrum having peaks at 747, 1225, 1266, 1432, 1646, 1706,and 3343 cm⁻¹±1 cm⁻¹; or both.
 14. A crystalline molecular complex oftadalafil and propylparaben of claim 4, wherein the molecular complex ischaracterized by: an X-ray powder diffractogram having peaks at 5.2,10.5, 15.3, 18.7, 20.6, 22.0, and 24.5 °2θ±0.2 °2θ; an infra-redspectrum having peaks at 747, 1098, 1271, 1433, 1645, 1700, and 3338cm⁻¹±1 cm⁻¹; or both.
 15. A pharmaceutical composition comprising acrystalline molecule complex of tadalafil and methyl and propylparabenof claim 13 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition comprising a crystalline molecular complex oftadalafil of claim 1 and a pharmaceutically acceptable carrier.
 17. Apharmaceutical composition comprising a crystalline molecule complex oftadalafil and methyl and propylparaben of claim 14 and apharmaceutically acceptable carrier.